NDLI: Structure of rat BCKD kinase: Nucleotide-induced domain communication in a mitochondrial protein kinase

Content Provider	PubMed Central
Author	Machius, Mischa Chuang, Jacinta L. Wynn, R. Max Tomchick, Diana R. Chuang, David T.
Copyright Year	2001
Abstract	Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain α-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain α-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. Unlike PHKs, BCK dimerizes through direct interaction of two opposing nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by both potassium and magnesium. Binding of ATP induces disorder–order transitions in a loop region at the nucleotide-binding site. These structural changes lead to the formation of a quadruple aromatic stack in the interface between the nucleotide-binding domain and the four-helix bundle domain, where they induce a movement of the top portion of two helices. Phosphotransfer induces further ordering of the loop region, effectively trapping the reaction product ADP, which explains product inhibition in mPKs. The BCK structure is a prototype for all mPKs and will provide a framework for structure-assisted inhibitor design for this family of kinases.
Related Links	http://dx.doi.org/10.1073/pnas.201220098
Ending Page	11223
Page Count	6
Starting Page	11218
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	20
Volume Number	98
Language	English
Publisher	The National Academy of Sciences
Publisher Date	2001-09-25
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

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